DESCRIPTION (verbatim from applicant's abstract): Over the past 20 years, medicinal chemists have synthesized many peptide mimetics (e.g., HIV protease inhibitors, glycoprotein (gp) IIb/IIIa receptor antagonists) with novel therapeutic indications (e.g., antiviral (AIDS), antithrombotic agents). These peptide mimetics contain structural features that stabilize them to hydrolytic pathways of metabolism and/or endow them with unique structural features that optimize their interactions with their macromolecular target (e.g., bioisosteres of amide bonds, turn mimetics). However, because of their poor biopharmaceutical properties (e.g., low permeation through the intestinal mucosa and high clearance by the liver), peptide mimetics often exhibit less than optimal oral bioavailability. Even when peptide mimetics are administered parenterally, they are in general rapidly cleared by the liver and tend not to gain access to important target areas (e.g., brain). Therefore, this research program is focused on elucidating what effects various amide bond bioisosteres and conformational constraints have on the permeation of peptide mimetics through the intestinal mucosa and the blood-brain barrier (BBB) and on their first pass clearance by the liver. Of particular interest are pathways that involve transporter proteins which either facilitate permeation across the intestinal mucosa (e.g., oligopeptide transporter) or restrict permeation across the intestinal mucosa and the BBB and facilitate clearance by the liver (e.g., multidrug resistance associated protein (MDR1) and multidrug resistance associated proteins (MRP1, MRP2)). The primary objectives of this research program for the next grant period are: (1) to elucidate the structure-transport relationships for a series of model peptide mimetics containing commonly used bioisosteres and conformational constraints with the efflux transporters (MDR1, MRP1, MRP2) and with the oligopeptide transporter; and (2) to determine what impact substrate activity for these transporters have on the in vivo biopharmaceutical properties of therapeutic peptide mimetics (e.g., HIV protease inhibitors, gpIIb/IIIa receptor antagonsits). The knowledge forthcoming from this research program should help medicinal chemists to rationally design peptide mimetics with improved biopharmaceutical properties.